The present invention relates to the healing of bone fractures, non-unions, and pseudoarthroses, and to the induction of an increase in bone mass.
Bones are important organs of the human body. On the one hand, they act as supports, and on the other hand, they serve as a storage facility for calcium and phosphorus. These two elements are present in bone in the form of apatite, a mineral. Depending upon other conditions in the body, calcium and phosphorus may be introduced or removed by hormonal regulation. For example, the body keeps a relatively constant level of calcium in the blood, because important biological activities such as contraction of muscles, beating of the heart, and clotting of blood require quite constant blood levels of calcium.
When the blood calcium level drops, more calcium is taken out of the bones to maintain the appropriate level. When the blood calcium returns to normal, increased amounts of calcium are no longer taken from the bones.
Living bone contains a protein framework (the osteoid matrix) in which the calcium salts are deposited. Bone, like many other tissues of the body, is constantly rebuilt or remodeled. Old bone is torn down, resorbed and replaced with new bone. The cells affecting the removal of calcium and phosphorus from bones are the osteoclasts. Those which deposit calcium and phosphorus in bone are osteoblasts. Thus, the building of bones by the osteoblasts takes place by the initial formation of the osteoid matrix which consists primarily of collagens (a fibrous protein) which is surrounded by proteoglycans and glycoproteins. Subsequent to formation, the matrix is enclosed by apatite to combine the desirable properties of the elastic fibers and the hard mineral substance.
As mentioned above, the osteoclasts are bone decomposing cells. They are generally multinuclear cells provided with numerous different enzyme activities. The enzymes and the acidity of the osteoclasts facilitate the decomposition of bone by on the one hand, dissolving the mineral thereby releasing ionic calcium and phosphate, and on the other, decomposing the organic matrix.
In intact, healthy bones, osteoblasts and osteoclasts coexist and both are active. This means that in healthy bone, a dynamic equilibrium is present between the osteoclast activity (bone decomposition) and osteoblast activity (bone building). Thus, over time, the average bone mass remains constant. Interference with this equilibrium leads either to a decrease or increase in bone mass.
Disturbances in this equilibrium can either be localized (a fracture) or generalized (osteopathies) such as for example, osteoporosis, osteomalacia, hyperparathyroidism and Paget's disease.
When a bone is fractured, there is generally tearing of small blood vessels causing bleeding at the fracture site. Bleeding occurs between the bone fragments and into the marrow cavity, as well as under the periosteum (the thin, tough fibrous membrane which covers the outer surface of the bone). This collection of blood and serum forms a clot which is called the "fracture-hematoma". The fracture-hematoma plays a very important role in fracture repair. The fracture-hematoma first undergoes a repair process which is similar to that which occurs in injuries of other tissues. This is known as organization of the clot. In the first few days there is rapid growth into the clot of cellular granulation tissue composed of fibroblasts and new fine capillary blood vessels. In about a week, small areas of young bone begin to be formed in an irregular pattern about these capillary blood vessels.
In addition to this organization of the clot by fibrous granulation tissue, there is a proliferation or multiplication of both osteoblasts and chondroblasts (cartilage-forming cells). Both new bone and new cartilage are laid down. This eventually forms the "callus", not only between the bone fragments but also under the periosteum and around the fracture site. At the same time that this new cartilage and new bone is being formed, all devitalized bone from the ends of the fracture fragments is being absorbed by osteoclasts, to be replaced by new bone.
The new cartilage which is formed in the callus is usually ultimately transformed into bone. Sometimes, however, cartilage formation predominates and little or no new bone is formed. This can happen when there is too much mobility between the fracture fragments. As a result, the fracture does not unite and a false joint (pseudoarthrosis) results. For this reason, immobilization of the fragments to prevent motion between them is essential during the healing stage of a fracture.
The primary callus which is first formed is fibrous at first and later becomes ossified. Primary boney callus is usually complete in some five to seven weeks after injury, but mineralization by deposit of calcium salts is not completed. It usually takes about two to four weeks longer, on the average, to complete mineralization so that the fracture fragments are united by solid bone. This time schedule varies for the different bones and can be much longer before bony union occurs. While this is referred to as "clinical union", this primary bone callus is a primitive type of solid bone and is actually only a temporary repair. Eventually, the adult type of lamellar bone must be formed in its place, and the original microscopic architecture of the bone must be restored.
Adult lamellar bone with its Haversian systems and medullary cavity forms very slowly. It requires for its formation the existing model of primitive new bone which the primary bony callus supplies. By the slow and continuous process of absorption and replacement, new adult bone is laid down in place of primary callus. Eventually, the parallel lamellar pattern of adult bone with its Haversian systems is restored and the marrow cavity which was temporarily occluded is recanalized. Excess callus is absorbed, thus restoring the original contour of the bone. It is only at this stage that anatomical healing is complete. This entire process takes a year or even longer for a major bone.
Unfortunately, various circumstances may interfere with fracture repair. One of the common interferences is loss of the fracture-hematoma. Since the fracture-hematoma plays the stellar role in the healing of a fracture, if this hematoma does not form, or is lost or escapes, the normal healing process is delayed or sometimes does not even occur. For example, this happens in compound fractures in which bleeding is to the outside and not within a closed space and thus no clot forms, and in surgical reduction of a fracture, for the same reason. This is one reason why closed reduction of a fracture is preferred if it is possible by this means to obtain and maintain good alignment and contact of the fracture fragments.
Because of the relatively long duration of impaired function resulting from a bone fracture, various methods have been suggested in the art for accellerating healing. For example, Duarte, U.S. Pat. No. 4,530,360, describes an apparatus and method for healing bone fractures, pseudoarthroses and the like with the use of ultrasound. An ultrasound transducer, in contact with the skin of the patient, transmits ultrasound pulses to the site of the bone defect. The nominal frequency of the ultrasound is 1.5 MHz, the width of each pulse varies between 10 and 2,000 microseconds, and the pulse repetition rate varies between 100 and 1000 Hz. The power level of the ultrasound is maintained below 100 milliwatts per square centimeter. It is stated therein that treatments which last about 20 minutes per day have been found to heal certain defects in less than two months.
Another method referred to in Duarte which has been employed in an attempt to accelerate healing is the application of direct current, on the order of 20 microamperes, at the site of a fracture. The cathode is usually applied at the site of the defect, whereas the anode is placed somewhere in the adjacent tissue or on the skin of the patient. Unfortunately, such arrangements are totally or partially invasive, which raises the concomitant possibility of infection. With non-invasive techniques, such as causing an externally generated electromagnetic field to pass through the fracture site to induce a current, precise alignment of the coils relative to the area to be treated is required, as well as treatment being required for 12 to 16 hours a day.
In the past, acoustic shock waves have been used to treat patients, but not in relation to bone. For example, shock wave treatments have been widely used to break up kidney stones to avoid invasion of the patient's body by instruments. Such treatments are described in publications such as U.S. Pat. No. 3,942,531 to Hoff et al. and Extracorporeal Shock Wave Lithotripsy, 1982, edited by Christian Chaussy and published by Karger AG of Basel, Switzerland. Generally, shock waves are generated exteriorly of the patient's body in a medium such as water and transmitted into the patient's body with suitable coupling to minimize energy absorption at the interface with the patient's skin. As pointed out in Chaussy, the shock waves (which differ from ultrasound wave inputs in that they have a very steep compression pressure rise front and little or no tension component) may travel through normal soft body tissue (except the lungs) at high pressure amplitudes without materially injuring the tissue.
As mentioned above, other interferences with the equilibrium between bone decomposition and bone building are osteopathies such as osteoporosis. Osteoporosis literally means "porous bone". While the outer form of the bones does not change unless there is a fracture, the bones have less substance and so are less dense. Osteoporosis is a common condition, affecting tens of millions of individuals around the world. For individuals over 45 years of age, approximately 70% of all fractures are related to osteoporosis.
In osteoporosis, bone mass decreases, causing bones to be more susceptible to fracture. A fall, blow, or lifting action that would not normally bruise or strain the average person can easily break one of more bones in someone with severe osteoporosis.
The spine, wrist and hip are the most common sites of osteoporosis-related fractures, although the disease is generalized, that is, it can affect any bone of the body. When the vertebrae are weakened, a simple action like bending forward to make a bed, or lifting a heavy pot roast out of the oven can be enough to cause a spinal compression fracture. These fractures often cause back pain, decreased height, and a humped back.
As a person grows during youth, bones are metabolically active, and calcium is deposited into bone faster than it is taken out. The deposition of calcium and phosphorus into bone peaks at about 35 years in men and women. At the time of peak bone mass, the bones are most dense and strong.
After a person's late thirties, calcium begins to be lost from bones faster than it is replaced, and bones become less dense. In addition, in general, as both women and men age, their bodies begin to absorb less calcium from food. In addition, particularly at the age of 40, several complex factors influence the quantity and quality of bone. These include: level of adult peak bone mass; rates of bone loss due to menopause and due to aging; certain systemic hormones (such as calcitriol, an active form of vitamin D; parathyroid hormone; and calcitonin); substances produced by the bones themselves; diet (especially calcium intake); intestinal and kidney function; and physical forces that act on the bone such as those caused by body weight and exercise.
Given the complexity of the factors that influence bone, there are believed to be many ways in which osteoporosis can develop. However, there appear to be at least two strong contributing factors which predominate: a drop in estrogen levels in women due to menopause and a chronically low intake of calcium.
Even in situations where a fracture of the bone has not occurred as a result of osteoporosis, osteoporosis may interfere with treatment of other conditions. For example, joint replacement therapies require relatively healthy bone to serve as support for the synthetic replacement. For example, in hip replacement operations, osteoporosis may preclude insertion of the shaft bearing the new ball in the femur because of decalcification.
One current method for recalcification of the femur prior to hip replacement surgery is to perform surgery to expose the femur and make multiple fractures in the bone to induce recalcification over a period of several weeks before conducting a second operation to effect hip replacement. Even when successful, it is not uncommon for erosion of bone to occur subsequent to replacement.
Similarly, where plates are applied to a bone to immobilize it while healing occurs, sufficient bone must be present to hold the plate in place.
Estrogen replacement therapy and increased calcium intake are currently commonly prescribed for osteoporosis. However, generally such treatments are designed to prevent rather than treat osteroprosis. A need continues to exist for drugs and techniques that can prevent osteoporosis as well as treat it after it has occurred.